Gene mutations trump histology in predicting outcomes for rare childhood muscle cancer
A multi-center study of 470 children with alveolar rhabdomyosarcoma finds that specific genetic fusions are better predictors of survival than traditional tumor classification. The findings could reshape how clinicians stratify treatment intensity and help pharmaceutical companies identify patient populations most likely to benefit from targeted therapies.
Originaltitel: Prognostic factors in patients with localized and metastatic alveolar rhabdomyosarcoma: A report from two studies and two registries of the Cooperative Weichteilsarkom Studiengruppe CWS
<p>Background</p><p>The histologic classification of rhabdomyosarcoma (RMS) as alveolar (aRMS) or embryonal (eRMS) is of prognostic importance, with the aRMS being associated with a worse outcome. Specific gene fusions (<em>PAX3/7</em><em>::</em><em>FOXO1</em>) found in the majority of aRMS have been recognized as markers associated with poor prognosis and are included in current risk stratification instead of histologic subtypes in localized disease. In metastatic disease, the independent prognostic significance of fusion status has not been definitively established. The objective of this analysis was to evaluate survival outcomes of patients with localized and metastatic aRMS and its association with fusion status and subtype (<em>PAX3/7</em><em>::</em><em>FOXO1</em>, <em>FOXO1</em> break), and clinical prognostic factors.</p><p>Methods</p><p>A total of 470 patients with aRMS ≤21 years of age enrolled in two CWS-trials and two registries was eligible for the analysis.</p><p>Results</p><p>The 5-year event-free survival (EFS) and overall survival (OS) rates for all patients with localized vs. metastatic tumors were: 56% and 65% vs. 18% and 22%, respectively. Of the 368 (78%) tumors tested, specific fusion was found in 330 (90%), considered “fusion positive” FP (<em>PAX3</em><em>::</em><em>FOXO1</em> in 280, <em>PAX7</em><em>::</em><em>FOXO1</em> in 49, <em>FOXO1</em> break in 59 tumors). In patients with localized tumors, univariate analysis revealed that clinical group, tumor invasiveness (T1 vs.T2), regional lymph node involvement (N0 vs. N1) and <em>FOXO1</em> fusion were significantly associated with EFS and OS, tumor size and <em>PAX</em> variant with OS only. In patients with metastatic aRMS, age, bone/marrow (B/BM) metastases, <em>FOXO1</em> fusion and <em>PAX</em> variant were associated with EFS and OS, T status with OS only. Multivariate analysis identified <em>PAX3</em><em>::</em><em>FOXO1</em> fusion as an independent adverse prognostic factor for EFS in patients with localized disease and for EFS and OS in patients with metastatic disease, B/BM metastases for EFS.</p><p>Conclusion</p><p><em>PAX3</em><em>::</em><em>FOXO1</em> fusion should replace <em>FOXO1</em> fusion as an adverse prognostic factor in risk stratification. The prognostic relevance of <em>PAX7</em><em>::</em><em>FOXO1</em>-positive and <em>FOXO1</em> fusion negative aRMS, along with the clinical factors described in this report, allows further refinement of risk assessment of patients with localized and metastatic aRMS.</p>